Since the first cases of acquired immunodeficiency syndrome (AIDS) were reported in 1981, infection with human immunodeficiency virus (HIV) has grown to pandemic proportions, resulting in an estimated 65 million infections and 25 million deaths. See Aug. 11, 2006, MMWR 55(31):841-844 (Center for Disease Control and Prevention). Protease inhibitors represent an important class of compounds used to treat individuals infected with HIV, although these compounds can also treat individuals suffering from other viral infections (e.g., Hepatitis C).
With respect to HIV, protease inhibitors act to inhibit the viral proteases that are necessary for the proteolytic cleavage of the gag and gag/pol fusion polypeptides necessary for the generation of infective viral particles. Thus, by inhibiting this proteolytic cleavage, protease inhibitors diminish the ability of larger HIV-fusion polypeptide precursors to from the mature form of protein necessary for effective viral replication. McQuade et al. (1990) Science 247(4941):454-456.
Protease inhibitor-based therapy is acknowledged as an initial treatment for patients presenting symptomatic HIV disease and in non-symptomatic patients after the CD4 cell count is below 350/μL but before a level of 200/μL. Hammer et al. (2006) JAMA 296(7):827-843. In such cases, a protease inhibitor-based regimen will include a protease inhibitor (typically boosted with ritonavir) along with a combination of two nucleoside (or nucleotide) reverse transcriptase inhibitors. Id.
Although protease inhibitors serve an important role in treating patients suffering from HIV, their use has been hampered by challenges associated with (among other things) extremely poor aqueous solubility and extensive metabolism. One approach suggested to address these drawbacks includes preparing prodrug forms of protease inhibitors, such as acyl and carbamotoyl glucose-containing prodrugs (Rouquayrol et al. (2001) Carbohydr. Res. 336:161-180) and relatively large PEG-based prodrugs (Gunaseelan et al. (2004) Bioconjugate Chem. 15:1322-1333). Although potentially addressing some of the disadvantages associated with protease inhibitors, prodrug approaches necessarily result in the return of the original molecule, often along with its associated drawbacks. For example, it is not believed that a prodrug approach would adequately solve the problems associated the extensive metabolism typically observed with protease inhibitors.
The present invention seeks to address this and other needs in the art.